Cefuroxime axetil is the 1-acetoxyethyl ester of cefuroxime, a cephalosporin antibiotic with a broad spectrum of activity against gram-positive and gram-negative microorganisms. This compound, as well as many other esters of cefuroxime, are disclosed and claimed in U.S. Pat. No. 4,267,320 (Gregson et al.; May 12, 1981). According to this patent, the presence of an appropriate esterifying group, such as the 1-acetoxyethyl group of cefuroxime axetil, enhances absorption of cefuroxime from the gastrointestinal tract, whereupon the esterifying group is hydrolyzed by enzymes present in the human body. Because of the presence of an asymmetric carbon atom, cefuroxime axetil can be produced as R and S diastereoisomers, or as a racemic mixture of the R and S diastereoisomers. U.S. Pat. No. 4,267,320 discloses conventional methods for preparing a mixture of the R and S isomers in crystalline form, as well as for separating the individual R and S diastereoisomers.
U.S. Pat. No. 4,562,181 (Crisp et al.; Dec. 31, 1985), and the related U.S. Pat. No. 4,820,833 (Apr. 11, 1989); U.S. Pat. No. 4,994,567 (Feb. 19, 1991); and U.S. Pat. No. 5,013,833 (May 7, 1991), disclose that cefuroxime axetil in amorphous form, essentially free from crystalline material and having a purity of at least 95% aside from residual solvents, has a higher bioavailability than the crystalline form while also having adequate chemical stability. These patents disclose that highly pure cefuroxime axetil can be recovered in substantially amorphous form from a solution containing cefuroxime axetil by spray drying roller drying, or solvent precipitation. The preferred method is spray drying. In each case crystalline cefuroxime axetil is dissolved in an organic solvent and the cefuroxime axetil is recovered from the solution in a highly pure, substantially amorphous form by one of the foregoing methods.
For purposes of patient safety, it is highly desirable to limit the amount of residual solvent present in any medicament administered to a patient. Therefore, it is an objective of the present invention to obtain a highly pure, substantially amorphous form of cefuroxime axetil in admixture with one or more pharmaceutically acceptable excipients without the use of organic solvents as have been heretofore used. Preparing highly pure cefuroxime axetil in substantially amorphous form provides benefits with respect to safety, health, and environmental considerations. Thus, the amorphous product should be at least as free of residual solvents as the starting crystalline material.
In accordance with the present invention, a method is disclosed for preparing highly pure cefuroxime axetil in substantially amorphous form in admixture with one or more pharmaceutically acceptable excipients. The method of the present invention comprises forming a mixture of crystalline cefuroxime axetil and the pharmaceutically acceptable excipient(s), and subjecting this mixture to milling action, whereby a composition is obtained in which the cefuroxime axetil has a purity by chromatographic analysis (chemical purity) of at least 95%, and the cefuroxime axetil is substantially free of any crystalline material, i.e., contains less than about 5% crystalline material. The amorphous cefuroxime axetil made in accordance with this invention may comprise either of the R or S diastereoisomers, or a mixture of the two. Desirably the particle size of the milled material is less than 2 xcexcm.
The milling may be carried out manually using a mortar and pestle. Alternatively, the milling may be carried out using commercially available milling machines, such as the ones described herein below.